This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic nephropathy, with the exception of the genetics of diabetic nephropathy and our participation in multicenter clinical trials, is now reported under this single project. In the last year, we continued to work with an international consortium known as the CKD Prognosis Consortium that is examining the prognostic implications of low estimated glomerular filtration rate and elevated albuminuria for mortality, kidney disease, and cardiovascular outcomes. Using data from numerous cohorts, the Consortium reported in JAMA that a more moderate decline in estimated glomerular filtration rate may be a useful endpoint for clinical trials of renoprotection in early kidney disease. A goal of the Consortium is to convince the Food and Drug Administration to add this endpoint to the group of currently acceptable endpoints for clinical trials of renoprotection that now include end-stage renal disease and doubling of the serum creatinine concentration. In a paper published in the Journal of the American Society of Nephrology, we reported that glomerular miR-21 expression is positively associated with elevated urinary albumin excretion in patients with diabetic kidney disease and that loss of the microRNA miR-21 is associated with accelerated glomerular damage and podocyte apoptosis in a mouse model of diabetic kidney disease as well as in Tgfb1-transgenic mice. These findings suggest a protective role of miR-21 in glomerular injury and further underscore the context-dependent functions of miR-21 and complex interaction with TGF&#946;-signaling. In a paper published in the American Journal of Epidemiology, we reported an association of arsenic exposure with development of type 2 diabetes in a population of American Indians at high risk for type 2 diabetes. This population consumes little seafood and lives where drinking water has moderately high inorganic arsenic concentrationssufficiently high so that methylation capacity and arsenic species could be measured in the urine. Using several accepted approaches to eliminate potential confounding by organic arsenic in the analysis, we found that moderately elevated exposure to inorganic arsenic may predict type 2 diabetes in this population. Larger studies that include measures of these arsenic species are required to confirm this finding. Regardless of the outcome of these studies, arsenic exposure should be reduced to protect community members from its other well established health effects. Finally, in a paper published in the Journal of the American Society of Nephrology, we reported an important role of podocyte sphingomyelin phosphodiesterase like 3b (SMPDL3b) expression levels in the pathogenesis of diabetic kidney disease. We found that high circulating soluble urokinase receptor (suPAR) levels are necessary but not sufficient to induce podocyte injury in diabetic kidney disease. We also demonstrate that in the presence of high serum suPAR levels, podocyte SMPDL3b expression levels will determine the fate of the podocyte. We concluded that increases in suPAR levels instill pathological signals on podocytes. In addition to the removal or neutralization of suPAR, our study suggests that therapeutic targeting of SMPDL3b expression in podocytes may prove beneficial in the treatment of diabetic kidney disease.